Adiponectin has been well established as an insulin sensitizer to suppress glucose production and regulate hepatic lipid metabolism. However, the molecular mechanisms underlying adiponectin action remain largely unknown. Our laboratory identified for the first time an adiponectin receptor interactive protein, APPL1, which plays an essential role in adiponectin signaling. Subsequently, we showed that APPL2, an isoform of APPL1, acts as integrated Yin-Yang regulatory machinery with APPL1 to regulate adiponectin signaling in cells. To elucidate the mechanisms by which APPL isoforms regulate adiponectin signaling, we screened a yeast two-hybrid cDNA library using APPL2 as bait. This screening led to identification of TCTP as a binding protein that interacts with APPL isoforms. Based on our preliminary studies, we hypothesize that TCTP is a key regulator of adiponectin signaling in the liver and its interaction with APPL isoforms may provide a mechanism underlying obesity-induced down-regulation of adiponectin signaling. Impairment of adiponectin signaling together with reduced level of adiponectin in obesity and type 2 diabetes play important roles in development of insulin resistance. Understanding the mechanisms underlying TCTP-regulated adiponectin signaling may lead to identification of novel and effective therapeutic strategies for the prevention and treatment of metabolic disorders.